Quinoxalines, a process for their preparation and their use

ABSTRACT

Disclosed are quinoxalinone compounds of the formula I or Ia ##STR1## and physiologically tolerated salts and prodrugs thereof, in which n=zero, one or two; 
     R 1  =fluorine, chlorine, hydroxyl or C 1  -C 3  -alkoxy; R 2  =C 1  -C 4  -alkyl which is unsubstituted or is substituted by hydroxyl, C 1  -C 4  -alkoxy or C 1  -C 4  -alkylthio; R 3  =C 1  -C 6  -alkyloxycarbonyl or C 2  -C 6  -alkenyloxycarbonyl, and X=oxygen, sulfur or selenium, a process for their preparation and pharmaceutical compositions containing the compounds.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to quinoxalines, to a process for theirpreparation, and to their use as virustatic agents, in particular fortreating infections with the human immunodeficiency virus (HIV).

2. Description of Related Art

European Patent Application EP-509398-A describes quinoxalinederivatives for treating infections with the human immunodeficiencyvirus (HIV).

SUMMARY OF THE INVENTION

It has now been found, surprisingly, that a group of speciallysubstituted quinoxalines of the formula I, ##STR2## and their tautomericforms of the formula Ia ##STR3## and also their physiologicallytolerated salts or prodrugs exhibit an antiviral effect, in particularagainst retroviruses, such as, for example, human immunodeficiency virus(HIV).

In the novel compounds of the formula I or Ia:

1) n is zero, one or two,

R¹ is fluorine, chlorine, hydroxyl or C₁ -C₃ -alkoxy,

R² is C₁ -C₄ -alkyl which is optionally substituted by hydroxyl, C₁ -C₄-alkoxy or C₁ -C₄ -alkylthio,

R³ is C₁ -C₆ -alkyloxycarbonyl or C₂ -C₆ -alkenyloxycarbonyl,

X is oxygen, sulfur or selenium.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

In a preferred group of compounds of the formula I or Ia:

2) n is zero or one,

R¹ is fluorine, chlorine, hydroxyl or C₁ -C₃ -alkoxy,

R² is C₁ -C₄ -alkyl which is optionally substituted by hydroxyl, C₁ -C₄-alkoxy or C₁ -C₄ -alkylthio,

R³ is C₁ -C₄ -alkyloxycarbonyl or C₂ -C₄ -alkenyloxycarbonyl,

X is oxygen or sulfur.

In another preferred group of compounds of the formula I or Ia:

3) n is zero or one,

R¹ is fluorine, chlorine, methoxy, ethoxy or propoxy,

R² is methylthiomethyl, ethyl or propyl, or C₁ -C₂ -alkyl which issubstituted by hydroxyl or C₁ -C₄ -alkoxy,

R³ is C₁ -C₄ -alkyloxycarbonyl or C₂ -C₄ -alkenyloxycarbonyl,

X is oxygen or sulfur.

Compounds of the formula I or Ia, as described above, are of veryparticular importance wherein the said substituents have the followingmeanings:

4) n is zero or one,

R¹ is fluorine, chlorine, methoxy or ethoxy,

R² is methylthiomethyl, ethyl or propyl, or C₁ -C₂ -alkyl which issubstituted by hydroxyl or C₁ -C₄ -alkoxy,

R³ is C₁ -C₄ -alkyloxycarbonyl or C₂ -C₄ -alkenyloxycarbonyl,

X is oxygen or sulfur.

The compoundS-4-isopropoxycarbonyl-6-methoxy-3-(methylthiomethyl)-3,4-dihydroquinoxalin-2(1H)-thione(Ex. 85) is of very particular importance. The compounds of the formulaeI and Ia possess an asymmetric carbon atom which is in the so-called Sconfiguration.

It has now been found, surprisingly, that the novel compounds possess anantiviral effect which is markedly increased to an extent which wasunexpected. It has furthermore been found that the pure enantiomers aremarkedly easier to dissolve than are the associated racemic compounds.The latter exist as genuine racemates, i.e. as 1:1 compounds of the twoenantiomers having individual physical properties.

As a consequence of this, the pure enantiomers are markedly betterabsorbed following oral administration in animal experiments. This is animportant prerequisite for the development of a novel pharmaceutical.

It is well known that it is of particular importance that high bloodlevels can be reached in order to achieve a pharmacological orchemotherapeutic effect which is as powerful as possible.

In view of the fact that it has not been possible to reach blood levelswhich are adequate for suppressing viral replication when using many ofthe virustatic agents which have potential against HIV owing to the lowbioavailability of these agents following oral administration, the novelcompounds represent antiviral agents of superior activity andconsequently represent a therapeutic advance.

The pure enantiomers of the compounds of the formulae I and Ia caneither be directly prepared by known methods, or in analogy with knownmethods, or else separated subsequently.

The compounds of the formulae I and Ia can be prepared by known methodsor by modifications thereof (see, for example, EP-509398-A, Rodd'sChemistry of Carbon Compounds, S. Coffey, M. F. Ansell (editors);Elsevier, Amsterdam, 1989; vol. IV part IJ, pp. 301 to 311. HeterocyclicCompounds, R. C. Elderfield (editor); Wiley, New York, 1957; vol. 6, pp.491 to 495).

The present invention furthermore relates to a process for preparingcompounds of the formulae I or Ia, as explained above in 1) to 4).

The process comprises:

A) for preparing compounds of the formula I in which X is oxygen and theradicals R¹, R² and R³ are defined as in 1) to 4), reacting a compoundof the formula II, ##STR4## where the definitions mentioned in 1) to 4)apply to R¹ and R², with a compound of the formula III

    R.sup.3 --Z                                                (III)

where R³ has the meanings mentioned above in 1) to 4) and Z is a leavinggroup such as, for example, chlorine;

or comprises:

B) for preparing compounds of the formula I, in which X is sulfur andR¹, R² and R³ are defined as in 1) to 4), comprising the step ofreacting a compound of the formula I, where X is oxygen and thedefinitions mentioned in 1) to 4) apply to R¹, R² and R³, with asulfurization reagent.

In the abovementioned method A), the reaction is preferably carried outusing a haloformic alkyl or alkenyl ester, a dialkyl or dialkenylcarbonate or a dialkyl or alkenyl dicarbonate. The substituent Z in theformula III is accordingly a suitable leaving group such as, forexample, chlorine, bromine or iodine, an alkoxy or alkenyloxy radical,or an alkoxycarbonyloxy or alkenyloxycarbonyloxy group. Z is preferablychlorine.

The reaction is expediently carried out in an inert solvent. Examples ofsuitable solvents are aromatic hydrocarbons, such as toluene or xylene;lower alcohols, such as methanol, ethanol or 1-butanol; ethers, such astetrahydrofuran or glycol dimethyl ether; dipolar aprotic solvents suchas N,N-dimethylformamide, N-methyl-2-pyrrolidone, acetonitrile,nitrobenzene or dimethyl sulfoxide; or mixtures of these solvents.Two-phase systems containing aqueous solutions of bases in the presenceof a phase transfer catalyst, such as, for example,benzyltriethylammonium chloride, are also possible.

It can be useful for a suitable base, for example an alkali metal oralkaline earth metal carbonate or hydrogen carbonate, such as sodiumcarbonate, calcium carbonate or sodium bicarbonate; an alkali metal oralkaline earth metal hydroxide, such as potassium hydroxide or bariumhydroxide; an alcoholate such as sodium ethoxide or potassiumtert-butoxide; an organolithium compound, such as butyllithium orlithium diisopropylamide; an alkali metal or alkaline earth metalhydride, such as sodium hydride or calcium hydride; an alkali metalfluoride, such as potassium fluoride; or an organic base, such astriethylamine, pyridine, 4-methylpyridine or 4-(dimethylamino)pyridine,to be present in order to capture the acid which is liberated during thereaction.

In many cases, it is appropriate to add an iodine salt, for examplepotassium iodide. The reaction is usually carried out at temperatures ofbetween -10° and 160° C., preferably at room temperature.

For this reaction, any nucleophilic substituents such as, for example,hydroxyl, mercapto or amino groups, with the exception of the 4 positionin compounds of the formula II, must be derivatized in a suitable mannerbefore carrying out the reaction or be provided with customaryprotective groups, which can subsequently be eliminated, such as, forexample, acetyl, benzyl, trityl, tetrahydropyranyl ortert-butoxycarbonyl.

2,4-Bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide(Lawesson's reagent), bis(tricyclohexyltin) sulfide, bis(tri-n-butyltin)sulfide, bis(triphenyltin) sulfide, bis(trimethylsilyl) sulfide orphosphorus pentasulfide may be preferably used as the sulfurizationreagent for the reaction as described above in B).

The reaction is expediently carried out in an organic solvent or asolvent mixture, at from -10° to 120° C., preferably at from roomtemperature to 60° C., and as far as possible under anhydrousconditions. Examples of suitable solvents are carbon disulfide, toluene,xylene, pyridine, dichloromethane, 1,2-dichloroethane, tetrahydrofuran,ethyl acetate or butyl acetate. When using the abovementioned tin orsilyl sulfides, it is expedient to carry out the sulfurization reactionin the presence of a Lewis acid such as boron trichloride.

Owing to its relatively low reactivity, the presence of a carbonyl groupin the R³ radical in the compounds of the formula I does not interferein this context, so that it is possible to carry out the sulfurizationselectively.

The quinoxalines of the formula II which are required as startingmaterials for the described syntheses are either known from theliterature or can be prepared by known methods, for example using themethods described in European Patent Application EP-509398-A.

The present invention also relates to the compounds as described in 1)to 4) as pharmaceuticals which are preferably used for treating viraldiseases, in particular diseases caused by HIV.

The present invention furthermore relates to pharmaceuticals whichcontain at least one novel compound and to the use of the said compoundsfor preparing pharmaceuticals, preferably for the treatment of viraldiseases, in particular for the treatment of diseases which are causedby HIV.

The present invention furthermore relates to the use of compounds of theabovementioned formula I or Ia for preparing pharmaceuticals fortreating viral diseases.

The compounds mentioned and explained in 1) to 4) above are preferredfor this use.

The novel pharmaceuticals may be administered to a host in need thereofenterally (orally), parenterally (intravenously), rectally,subcutaneously, intramuscularly or locally (topically).

They can be administered in the form of solutions, powders (tablets andcapsules, including microcapsules), ointments (creams or gels) orsuppositories. Pharmaceutically acceptable carriers including customaryliquid or solid fillers and extenders, solvents, emulsifiers,lubricants, taste corrigents, dyes and/or buffering substances aresuitable for use as auxiliary substances for formulations of thisnature.

As an expedient dosage, from 0.1 to 10, preferably from 0.2 to 8, mg areadministered per kg of body weight once or several times daily. Thedosage units employed expediently depend on the relevantpharmacokinetics of the substance or the pharmaceutical preparationwhich is used.

The dosage unit of the novel compounds which is used is, for example,from 1 to 1500 mg, preferably from 50 to 500 mg.

The novel compounds may also be administered to a host in need thereofin combination with other antiviral agents such as, for example,nucleoside analogs, protease inhibitors or adsorption inhibitors,immunostimulants, interferons, interleukins and colony-stimulatingfactors (e.g. GM-CSF, G-CSF and M-CSF).

Pure enantiomers are understood to mean those compounds in which theenantiomer ratio is at least 95:5, preferably at least 97:3.

The present invention is explained in more detail by the followingexamples and by the content of the patent claims.

EXAMPLE 1 N-(5-Fluoro-2-nitrophenyl)-S-methyl-L-cysteine

16.2 g of (-)-S-Methyl-L-cysteine (0.1 mol) are suspended in a mixtureof 120 ml of water and 120 ml of acetone in a four-necked flask underN₂. 30.4 ml (22.2 g) of triethylamine (0.22 mol) are added rapidly whilestirring. 15.9 g of 2,4-difluoronitrobenzene (0.1 mol) are added, withfurther stirring, to the resulting yellow solution. The mixture isheated to reflux for 7.5 hours while stirring (orange-colored solution)and the acetone is then stripped off under reduced pressure on a rotaryevaporator; the aqueous residue is transferred to a separating funneland extracted 2× with approximately 50 ml of methyl tert-butyl ether(MTB ether). This extract is composed, in the main, of2,4-difluoronitrobenzene and is discarded. The aqueous phase istransferred to a four-necked flask and 150 ml of MTB ether are added toit, after which the mixture is adjusted, while being cooled (<25° C.),to pH 1 with approximately 25 ml of 38% sulfuric acid. The mixture isthen stirred thoroughly until clear phases are formed. The ether phaseis separated off and the aqueous phase is extracted once again with 50ml of MTB ether. The extracts are dried over sodium sulfate andevaporated on a rotary evaporator. The yield comprises 27 g of a yellowoil which soon solidifies. M.p. 147° (from water/methanol).

MS: chemical ionization, (M+H)⁺ =275

    ______________________________________                                        Analysis:       Calculated                                                                             Found                                                ______________________________________                                        C               43.8%    43.8%                                                H               4.0%     4.1%                                                 N               10.2%    10.0%                                                S               11.7%    11.3%                                                ______________________________________                                    

EXAMPLE 2 N-(5-Methoxy-2-nitrophenyl)-S-methyl-L-cysteine

27 g of N-(5-fluoro-2-nitrophenyl)-S-methyl-L-cysteine (0.1 mol) fromExample 1 are dissolved in 150 ml of absolute methanol in a four-neckedflask, and 14.4 g of 95% sodium methoxide (0.25 mmol) are added inportions, within the space of 20 minutes and under argon, to thissolution while stirring well and while cooling by means of an ice bath.The mixture is then heated to reflux for 2 hours while stirring. TLCmonitoring then indicates that the reaction is complete.

Most of the methanol is stripped off under reduced pressure on a rotaryevaporator. 200 ml of ice water are added to the residue and thismixture is adjusted to a pH of 1 with approximately 25 ml of 38%sulfuric acid and then thoroughly stirred with 150 ml of MTB ether. Theether phase is separated off and the aqueous phase is extracted onceagain with 30 ml of MTB ether and subjected to rotary evaporation underreduced pressure.

Yield: 21.5 g of brown-red oil which slowly crystallizes.

MS: chemical ionization, (M+H)⁺ =287

HPLC: 99.3% of S-enantiomer

    ______________________________________                                        Analysis:       Calculated                                                                             Found                                                ______________________________________                                        C               46.2%    47.3%                                                H               4.9%     5.6%                                                 N               9.8%     9.1%                                                 S               11.1%    10.6%                                                ______________________________________                                    

EXAMPLE 3S-6-methoxy-3-(methylthiomethyl)-3,4-dihydroquinoxalin-2(1H)-one

20.7 g of the compound from Example 2 (0.065 mol) are dissolved in 250ml of methanol and hydrogenated under argon with 0.5 ml of glacialacetic acid and approximately 20 g of Raney nickel under standardpressure and at room temperature. The hydrogenation is complete when TLCis no longer able to detect any starting material. The mixture isfiltered with suction, while being overlaid with nitrogen, and thefilter residue is then washed with 100 ml of methanol.

The filter residue, including the catalyst, is thoroughly stirred, atfrom 45° to 50° C., with dimethylformamide (DMF), while being overlaidwith nitrogen, and this mixture is then once again filtered with suctionthrough a clarifying layer. The product-containing DMF solution isallowed to run directly into 1 l of ice water which is being stirred andto which 2 g of ascorbic acid have been added as an antioxidant. Duringthis procedure, the product results in the form of pale yellow crystals.These are filtered off with suction, washed with approximately 2 l ofwater then with 500 ml of ethanol and then with 300 ml of pentane, anddried over phosphorus pentoxide.

The yield is 10.8 g; a further 1.3 g can be obtained by concentratingthe filtrate.

M.p. from 186° to 187° C., yellow-grayish solid.

¹ H-NMR (200 MHz, d₆ -DMSO): δ=2.08 (s, 3H, SCH₃), 2.75 (dq_(AB), 2H,--CH₂ --S), 3.65 (s, 3H, MeO), 3.95 (m, 1H, CH), 6.05 (br, s, NH),6.1-6.7 (m, 3H, aromatics), 10.15 (s, 1H, amide).

MS: chemical ionization, (M+H)⁺ =239

HPLC: 97.5% purity, 98.2% of the S-enantiomer

Optical rotation: α!_(D) ²² =-42° (c=1 in acetone)

    ______________________________________                                        Analysis:       Calculated                                                                             Found                                                ______________________________________                                        C               55.5%    55.2%                                                H               5.9%     5.8%                                                 N               11.8%    11.7%                                                S               13.4%    13.3%                                                ______________________________________                                    

The following are obtained in an analogous manner:

EXAMPLE 4S-6-Ethoxy-3-(methylthiomethyl)-3,4-dihydroquinoxalin-2(1H)-one

Obtained from the compound of Example 1 using lithium ethoxide inethanol and carrying out reduction and ring closure in analogy withExample 2.

MS: chemical ionization, (M+H)⁺ =253

¹ H-NMR (200 MHz, d₆ -DMSO): ethoxy group δ=1.27 (t, 3H), 3.87 (q, 2H)

EXAMPLE 5S-3-(Methylthiomethyl)-6-propoxy-3,4-dihydroquinoxalin-2(1H)-one

Obtained from the compound of Example 1 using sodium propoxide inpropanol.

M.p. resin, MS: chemical ionization, (M+H)⁺ =267

¹ H-NMR (200 MHz, d₆ -DMSO): propoxy group δ=0.95 (t, 3H), 1.67 (q, 2H),3.79 (t, 2H)

EXAMPLE 6 S-3-(Methylthiomethyl)-3,4-dihydroquinoxalin-2(1H)-one

Obtained by using 2-fluoronitrobenzene in place of2,4-difluoronitrobenzene in Example 1.

M.p. 109° C., MS: chemical ionization, (M+H)⁺ =208

EXAMPLE 7S-6-Fluoro-3-(methylthiomethyl)-3,4-dihydroquinoxalin-2(1H)-one

Obtained by direct further use of the compound from Example 1 inreduction and ring closure reactions as in Example 3.

M.p. 149° C., MS: chemical ionization, (M+H)⁺ =243

EXAMPLE 8S-6-Chloro-3-(methylthiomethyl)-3,4-dihydroquinoxalin-2(1H)-one

Obtained by using 2,4-dichloronitrobenzene in place of2,4-difluoronitrobenzene in Example 1 and using sodium hydroxide andglycol monomethyl ether at reflux temperature.

M.p. 149° C., MS: chemical ionization, (M+H)⁺ =243

When other amino acids are used, for example, the correspondingcompounds of the formula II, in which the lacuna! substituent of theamino acid employed becomes the substituent R² in formula II, can beobtained in an analogous manner to that described in Examples 1 to 8:

                  TABLE 1                                                         ______________________________________                                         ##STR5##                                                                     Example No.                                                                              R.sup.1.sub.n                                                                            R.sup.2     M.p. °C.                             ______________________________________                                         9         H (n = 0)  C.sub.2 H.sub.5                                                                           Oil                                         10         H (n = 0)  C.sub.3 H.sub.7                                                                           Resin                                       11         H (n = 0)  C.sub.4 H.sub.9                                                                           Oil                                         12         H (n = 0)  HOCH.sub.2   82                                         13         6-Cl       C.sub.2 H.sub.5                                                                           120                                         14         6-Cl       C.sub.3 H.sub.7                                                                           75-77                                       15         6-Cl       C.sub.4 H.sub.9                                                                           Oil                                         16         6-F        C.sub.2 H.sub.5                                                                            93                                         17         6-F        C.sub.3 H.sub.7                                                                           Resin                                       18         6-F        HOCH.sub.2  134                                         19         6-CH.sub.3 O                                                                             C.sub.2 H.sub.5                                                                           Oil                                         20         6-CH.sub.3 O                                                                             C.sub.3 H.sub.7                                                                           138                                         21         6-CH.sub.3 O                                                                             C.sub.4 H.sub.9                                         22         6-CH.sub.3 O                                                                             HOCH.sub.2  125 decomp.                                 23         6-CH.sub.3 O                                                                             CH.sub.3 CH(OH)                                                                           156                                         24         6-CH.sub.3 O                                                                             CH.sub.3 OCH.sub.2                                                                        167                                         25         6-C.sub.2 H.sub.5 O                                                                      C.sub.2 H.sub.5                                         26         6-C.sub.2 H.sub.5 O                                                                      C.sub.3 H.sub.7                                         27         6-C.sub.2 H.sub.5 O                                                                      CH.sub.3 OCH.sub.2                                      28         6-C.sub.3 H.sub.7 O                                                                      C.sub.2 H.sub.5                                          28a       6-OH       CH.sub.3 SCH.sub.2                                                                        146                                         ______________________________________                                    

EXAMPLE 29S-4-Isopropoxycarbonyl-6-methoxy-3-(methylthiomethyl)-3,4-dihydroquinoxalin-2(1H)-one

11.9 g (0.05 mol) of the compound from Example 3 are suspended in 300 mlof methylene chloride under nitrogen. 7.0 g of 4-methylpyridine (0.075mol), as base, are added rapidly while stirring. 60 ml of a 1 molarsolution of isopropyl chloroformate in toluene (0.06 mol) are then addeddropwise at room temperature within the space of 30 minutes. During thisprocedure, the suspension slowly goes into solution. Monitoring by TLCindicates that the reaction is complete after from 4 to 6 hours at roomtemperature. The solution is acidified with 2N sulfuric acid, theorganic phase is separated off, and the aqueous phase is extracted oncemore with 50 ml of methylene chloride. After the solvents have beenevaporated off under reduced pressure, a semi-solid product remainswhich is recrystallized from diisopropyl ether while stirring.

Yield: 15.0 g, m.p. 115° C.

¹ H-NMR (200 MHz, d₆ -DMSO): δ=1.3 (2d, J=7 Hz, 6H, 2 isopropyl-CH₃),2.1 (s, 3H, SCH₃), 2.35+2.7 (dq_(AB), 2H, --CH₂ --S), 3.73 (s, 3H, MeO),4.87 (q, 1H, CH), 4.97 (m, J=7 Hz, 1H, isopropyl-CH), 6.7-7.25 (m, 3H,aromatics), 10.65 (s, 1H, amide).

MS: chemical ionization, (M+H)⁺ =325

HPLC: 98% purity, 99.9% of S-enantiomer

Optical rotation: α!_(D) ²² =39° (c=1 in methanol)

    ______________________________________                                        Analysis:       Calculated                                                                             Found                                                ______________________________________                                        C               55.6%    55.5%                                                H               6.2%     5.8%                                                 N               8.6%     8.4%                                                 S               9.8%     9.7%                                                 ______________________________________                                    

When, for example, compounds of the formula II, as mentioned, forexample, in Examples 3-28, are used, the following compounds of theformula I in which X═O can be obtained in an analogous manner to thatdescribed in Example 29 by reaction with the corresponding compounds ofthe formula III:

                  TABLE 2                                                         ______________________________________                                         ##STR6##                                                                     Ex-                                                                           am-                                                                           ple                                     M.p.                                  No.  R.sup.1.sub.n                                                                          R.sup.2     R.sup.3       °C.                            ______________________________________                                        30   H (n = 0)                                                                              C.sub.2 H.sub.5                                                                           COOCH(CH.sub.3).sub.2                                                                       163                                   31   H (n = 0)                                                                              C.sub.3 H.sub.7                                                                           COOCH(CH.sub.3).sub.2                                                                       117                                   32   H (n = 0)                                                                              C.sub.4 H.sub.9                                                                           COOCH(CH.sub.3).sub.2                                                                       120                                   33   H (n = 0)                                                                              HOCH.sub.2  COOCH(CH.sub.3).sub.2                               34   H (n = 0)                                                                              CH.sub.3 SCH.sub.2                                                                        COOCH(CH.sub.3).sub.2                                                                       119                                   35   6-Cl     C.sub.2 H.sub.5                                                                           COOCH(CH.sub.3).sub.2                                                                       145-                                                                          147                                   36   6-Cl     C.sub.3 H.sub.7                                                                           COOCH(CH.sub.3).sub.2                               37   6-Cl     C.sub.4 H.sub.9                                                                           COOCH(CH.sub.3).sub.2                               38   6-Cl     CH.sub.3 SCH.sub.2                                                                        COOCH(CH.sub.3).sub.2                                                                       105                                   39   6-F      C.sub.2 H.sub.5                                                                           COOCH(CH.sub.3).sub.2                                                                       123-                                                                          125                                   40   6-F      C.sub.3 H.sub.7                                                                           COOCH(CH.sub.3).sub.2                                                                       110                                   41   6-F      C.sub.4 H.sub.9                                                                           COOCH(CH.sub.3).sub.2                               42   6-F      CH.sub.3 SCH.sub.2                                                                        COOCH(CH.sub.3).sub.2                                                                       136                                   43   6-CH.sub.3 O                                                                           C.sub.2 H.sub.5                                                                           COOCH(CH.sub.3).sub.2                                                                       Oil                                   44   6-CH.sub.3 O                                                                           C.sub.3 H.sub.7                                                                           COOCH(CH.sub.3).sub.2                                                                       153                                   45   6-CH.sub.3 O                                                                           C.sub.4 H.sub.9                                                                           COOCH(CH.sub.3).sub.2                               46   6-CH.sub.3 O                                                                           HOCH.sub.2  COOCH(CH.sub.3).sub.2                                                                       Resin                                 47   6-CH.sub.3 O                                                                           CH.sub.3 CH(OH)                                                                           COOCH(CH.sub.3).sub.2                                                                       Resin                                 48   6-CH.sub.3 O                                                                           CH.sub.3 OCH.sub.2                                                                        COOCH(CH.sub.3).sub.2                                                                        98                                   49   6-C.sub.2 H.sub.5 O                                                                    C.sub.2 H.sub.5                                                                           COOCH(CH.sub.3).sub.2                               50   6-C.sub.2 H.sub.5 O                                                                    C.sub.3 H.sub.7                                                                           COOCH(CH.sub.3).sub.2                               51   6-C.sub.2 H.sub.5 O                                                                    CH.sub.3 OCH.sub.2                                                                        COOCH(CH.sub.3).sub.2                               52   6-C.sub.2 H.sub.5 O                                                                    CH.sub.3 SCH.sub.2                                                                        COOCH(CH.sub.3).sub.2                                                                       112                                   53   6-C.sub.3 H.sub.7 O                                                                    C.sub.2 H.sub.5                                                                           COOCH(CH.sub.3).sub.2                               54   6-C.sub.3 H.sub.7 O                                                                    CH.sub.3 SCH.sub.2                                                                        COOCH(CH.sub.3).sub.2                                                                       105                                   55   H (n = 0)                                                                              C.sub.2 H.sub.5                                                                           COOC(CH.sub.3)CH.sub.2                              56   H (n = 0)                                                                              CH.sub.3 SCH.sub.2                                                                        COOC(CH.sub.3)CH.sub.2                              57   6-Cl     C.sub.2 H.sub.5                                                                           COOC(CH.sub.3)CH.sub.2                                                                      143                                   58   6-Cl     C.sub.2 H.sub.5                                                                           COOCH.sub.2 CHCH.sub.2                                                                      122-                                                                          124                                   59   6-Cl     CH.sub.3 SCH.sub.2                                                                        COOC(CH.sub.3)CH.sub.2                                                                      182                                   60   6-Cl     CH.sub.3 SCH.sub.2                                                                        COOC.sub.3 H.sub.7                                                                           68                                   61   6-Cl     CH.sub.3 SCH.sub.2                                                                        COOC.sub.2 H.sub.5                                                                          143                                   62   6-F      C.sub.2 H.sub.5                                                                           COOC(CH.sub.3)CH.sub.2                                                                      125                                   63   6-F      C.sub.3 H.sub.7                                                                           COOC(CH.sub.3)CH.sub.2                              64   6-F      CH.sub.3 SCH.sub.2                                                                        COOC(CH.sub.3)CH.sub.2                              65   6-CH.sub.3 O                                                                           C.sub.2 H.sub.5                                                                           COOC(CH.sub.3)CH.sub.2                              66   6-CH.sub.3 O                                                                           C.sub.3 H.sub.7                                                                           COOC(CH.sub.3)CH.sub.2                              67   6-CH.sub.3 O                                                                           CH.sub.3 OCH.sub.2                                                                        COOC(CH.sub.3)CH.sub.2                              68   6-CH.sub.3 O                                                                           CH.sub.3 SCH.sub.2                                                                        COOC(CH.sub.3)CH.sub.2                                                                      152                                   69   6-CH.sub.3 O                                                                           CH.sub.3 SCH.sub.2                                                                        COOCH.sub.2 CH(CH.sub.3)C.sub.2 H.sub.5             70   6-C.sub.2 H.sub.5 O                                                                    C.sub.2 H.sub.5                                                                           COOC(CH.sub.3)CH.sub.2                              71   6-C.sub.2 H.sub.5 O                                                                    C.sub.3 H.sub.7                                                                           COOC(CH.sub.3)CH.sub.2                              72   6-C.sub.2 H.sub.5 O                                                                    CH.sub.3 OCH.sub.2                                                                        COOC(CH.sub.3)CH.sub.2                              73   6-C.sub.2 H.sub.5 O                                                                    CH.sub.3 SCH.sub.2                                                                        COOC(CH.sub.3)CH.sub.2                              74   H (n = 0)                                                                              C.sub.2 H.sub.5                                                                           COOC.sub.2 H.sub.5                                  75   H (n = 0)                                                                              C.sub.3 H.sub.7                                                                           COOC.sub.2 H.sub.5                                  76   H (n = 0)                                                                              CH.sub.3 SCH.sub.2                                                                        COOC.sub.2 H.sub.5                                  77   6-Cl     C.sub.2 H.sub.5                                                                           COOC.sub.2 H.sub.5                                  78   6-F      C.sub.2 H.sub.5                                                                           COOC.sub.2 H.sub.5                                                                          116                                   79   6-F      CH.sub.3 SCH.sub.2                                                                        COOC.sub.2 H.sub.5                                  80   6-CH.sub.3 O                                                                           C.sub.2 H.sub.5                                                                           COOC.sub.2 H.sub.5                                  81   6-CH.sub.3 O                                                                           CH.sub.3 OCH.sub.2                                                                        COOC.sub.2 H.sub.5                                  82   6-CH.sub.3 O                                                                           CH.sub.3 SCH.sub.2                                                                        COOC.sub.2 H.sub.5                                  83   6-C.sub.2 H.sub.5 O                                                                    C.sub.2 H.sub.5                                                                           COOC.sub.2 H.sub.5                                  84   6-C.sub.2 H.sub.5 O                                                                    CH.sub.3 SCH.sub.2                                                                        COOC.sub.2 H.sub.5                                  84a  6-OH     CH.sub.3 SCH.sub.2                                                                        COOCH(CH.sub.3).sub.2                                                                       182                                   84b  6-OH     C.sub.2 H.sub.5                                                                           COOCH(CH.sub.3).sub.2                                                                       201                                   84c  6-Cl     CH.sub.3    COOC.sub.2 H.sub.5                                                                          151                                   84d  6-Cl     C.sub.4 H.sub.9                                                                           COOC(CH.sub.3)CH.sub.2                                                                      158                                   84e  6-Cl     CH.sub.3 SCH.sub.2                                                                        COOC.sub.2 H.sub.5                                                                          143                                   84f  6-Cl     CH.sub.3 SCH.sub.2                                                                        COOC.sub.3 H.sub.7                                                                           68                                   84g  6-CH.sub.3 O                                                                           CH.sub.3 SCH.sub.2                                                                        COOCH(CH.sub.3)C.sub.2 H.sub.5                                                               86                                   84h  6-CH.sub.3 O                                                                           CH.sub.3 SCH.sub.2                                                                        COOCH.sub.2 CH(CH.sub.3).sub.2                                                               60                                   84i  6-F      CH.sub.3    COOCH(CH.sub.3).sub.2                                                                       151                                   84j  6-F      C.sub.2 H.sub.5                                                                           COOCH(CH.sub.3)C.sub.2 H.sub.5                                                              Resin                                 84k  6-F      C.sub.2 H.sub.5                                                                           COOCH.sub.3    50                                   84l  6-F      C.sub.2 H.sub.5                                                                           COOC.sub.4 H.sub.9                                                                           92                                   84m  6-F      C.sub.2 H.sub.5                                                                           COOCH.sub.2 CH(CH.sub.3).sub.2                                                               90                                   84n  6-F      CH.sub.2 OH COOCH(CH.sub.3).sub.2                                                                       Resin                                 84o  6-F      CH.sub.3 OCH.sub.2                                                                        COOCH(CH.sub.3).sub.2                                                                       114                                   ______________________________________                                    

EXAMPLE 85S-4-Isopropoxycarbonyl-6-methoxy-3-(methylthiomethyl)-3,4-dihydroquinoxalin-2(1H)-thione

16.1 g of the compound from Example 29 (0.05 mol) are dissolved in 200ml of dry dimethoxyethane, and 13 g of finely powdered phosphoruspentasulfide (0.06 mol) are added to this solution, under argon andwhile stirring, and the mixture is then stirred at room temperature.After 24 hours, the reaction is still not complete so that a further 4 gof phosphorus pentasulfide are added. After having been incubated atroom temperature for 24 hours, the mixture is stirred for a further 3hours at 30° C. The mixture is then filtered with suction through aclarifying layer in order to separate off solids, which are then washedwith dimethoxyethane. The collected filtrates are evaporated underreduced pressure. The dark oil which remains is taken up in 250 ml ofMTB ether and this solution is thoroughly stirred with 200 ml of asaturated solution of sodium hydrogen carbonate. The phases areseparated and the aqueous phase is extracted once again with 20 ml ofMTB ether. The organic extracts are dried over magnesium sulfate orsodium sulfate and subjected to rotary evaporation.

The yellow-brown oil which remains is dissolved in 30 ml of hotdiisopropyl ether. It crystallizes out when the solution is cooled whilebeing stirred. The crystals which have precipitated are washed with alittle diisopropyl ether and n-pentane and dried in a desiccator.

Yield 91.4 g, m.p. 103° C.

¹ H-NMR (200 MHz, d₆ -DMSO): δ=1.27 (2d, J=7 Hz, 6H, 2 isopropyl-CH₃),2.1 (s, 3H, SCH₃), 2.34+2.79 (dq_(AB), 2H, --CH₂ --S), 3.75 (s, 3H,MeO), 4.97 (m, J=7 Hz, 1H, isopropyl-CH), 5.25 (q, 1H, CH), 6.75-7.3 (m,3H, aromatics), 12.73 (s, 1H, thioamide).

MS: chemical ionization, (M+H)⁺ =341

HPLC. 99.6% purity, 99.4% of S-enantiomer

Optical rotation: α!_(D) ²² =18° (c=1 in methanol)

    ______________________________________                                        Analysis:       Calculated                                                                             Found                                                ______________________________________                                        C               52.9%    52.9%                                                H               5.9%     5.3%                                                 N               8.4%     8.3%                                                 S               18.8%    18.6%                                                ______________________________________                                    

When, for example, compounds of the formula I in which X═O, asmentioned, for example, in Examples 30 to 84, are used, the followingcompounds of the formula I in which X═S can be obtained in an analogousmanner to that described in Example 85 by reaction with thecorresponding sulfurization reagents:

                  TABLE 3                                                         ______________________________________                                         ##STR7##                                                                     Example                                 M.p.                                  No.    R.sup.1.sub.n                                                                          R.sup.2     R.sup.3     °C.                            ______________________________________                                         86    H (n = 0)                                                                              C.sub.2 H.sub.5                                                                           COOCH(CH.sub.3).sub.2                                                                     114                                    87    H (n = 0)                                                                              C.sub.3 H.sub.7                                                                           COOCH(CH.sub.3).sub.2                                                                     128                                    88    H (n = 0)                                                                              C.sub.4 H.sub.9                                                                           COOCH(CH.sub.3).sub.2                                                                      78                                    89    H (n = 0)                                                                              HOCH.sub.2  COOCH(CH.sub.3).sub.2                              90    H (n = 0)                                                                              CH.sub.3 SCH.sub.2                                                                        COOCH(CH.sub.3).sub.2                                                                     Oil                                    91    6-Cl     C.sub.2 H.sub.5                                                                           COOCH(CH.sub.3).sub.2                                                                     161                                    92    6-Cl     C.sub.3 H.sub.7                                                                           COOCH(CH.sub.3).sub.2                              93    6-Cl     C.sub.4 H.sub.9                                                                           COOCH(CH.sub.3).sub.2                              94    6-Cl     CH.sub.3 SCH.sub.2                                                                        COOCH(CH.sub.3).sub.2                                                                     124                                    95    6-F      C.sub.2 H.sub.5                                                                           COOCH(CH.sub.3).sub.2                                                                      93                                    96    6-F      C.sub.3 H.sub.7                                                                           COOCH(CH.sub.3).sub.2                                                                      60                                    97    6-F      C.sub.4 H.sub.9                                                                           COOCH(CH.sub.3).sub.2                              98    6-F      CH.sub.3 SCH.sub.2                                                                        COOCH(CH.sub.3).sub.2                                                                     122                                    99    6-CH.sub.3 O                                                                           C.sub.2 H.sub.5                                                                           COOCH(CH.sub.3).sub.2                                                                      74                                   100    6-CH.sub.3 O                                                                           C.sub.3 H.sub.7                                                                           COOCH(CH.sub.3).sub.2                                                                     140                                   101    6-CH.sub.3 O                                                                           C.sub.4 H.sub.9                                                                           COOCH(CH.sub.3).sub.2                             102    6-CH.sub.3 O                                                                           HOCH.sub.2  COOCH(CH.sub.3).sub.2                             103    6-CH.sub.3 O                                                                           CH.sub.3 CH(OH)                                                                           COOCH(CH.sub.3).sub.2                             104    6-CH.sub.3 O                                                                           CH.sub.3 OCH.sub.2                                                                        COOCH(CH.sub.3).sub.2                                                                     137                                   105    6-C.sub.2 H.sub.5 O                                                                    C.sub.2 H.sub.5                                                                           COOCH(CH.sub.3).sub.2                             106    6-C.sub.2 H.sub.5 O                                                                    C.sub.3 H.sub.7                                                                           COOCH(CH.sub.3).sub.2                             107    6-C.sub.2 H.sub.5 O                                                                    CH.sub.3 OCH.sub.2                                                                        COOCH(CH.sub.3).sub.2                             108    6-C.sub.2 H.sub.5 O                                                                    CH.sub.3 SCH.sub.2                                                                        COOCH(CH.sub.3).sub.2                                                                     Oil                                   109    6-C.sub.3 H.sub.7 O                                                                    C.sub.2 H.sub.5                                                                           COOCH(CH.sub.3).sub.2                             110    6-C.sub.3 H.sub.7 O                                                                    CH.sub.3 SCH.sub.2                                                                        COOCH(CH.sub.3).sub.2                                                                     Resin                                 111    H (n = 0)                                                                              C.sub.2 H.sub.5                                                                           COOC(CH.sub.3)CH.sub.2                            112    H (n = 0)                                                                              CH.sub.3 SCH.sub.2                                                                        COOC(CH.sub.3)CH.sub.2                            113    6-Cl     C.sub.2 H.sub.5                                                                           COOC(CH.sub.3)CH.sub.2                                                                    170                                   114    6-Cl     C.sub.2 H.sub.5                                                                           COOCH.sub.2 CHCH.sub.2                                                                    123                                   115    6-Cl     CH.sub.3 SCH.sub.2                                                                        COOC(CH.sub.3)CH.sub.2                                                                    128                                   116    6-Cl     CH.sub.3 SCH.sub.2                                                                        COOC.sub.3 H.sub.7                                117    6-Cl     CH.sub.3 SCH.sub.2                                                                        COOC.sub.2 H.sub.5                                118    6-F      C.sub.2 H.sub.5                                                                           COOC(CH.sub.3)CH.sub.2                            119    6-F      C.sub.3 H.sub.7                                                                           COOC(CH.sub.3)CH.sub.2                            120    6-F      CH.sub.3 SCH.sub.2                                                                        COOC(CH.sub.3)CH.sub.2                            121    6-CH.sub.3 O                                                                           C.sub.2 H.sub.5                                                                           COOC(CH.sub.3)CH.sub.2                            122    6-CH.sub.3 O                                                                           C.sub.3 H.sub.7                                                                           COOC(CH.sub.3)CH.sub.2                            123    6-CH.sub.3 O                                                                           CH.sub.3 OCH.sub.2                                                                        COOC(CH.sub.3)CH.sub.2                            124    6-CH.sub.3 O                                                                           CH.sub.3 SCH.sub.2                                                                        COOC(CH.sub.3)CH.sub.2                                                                    152                                   125    6-CH.sub.3 O                                                                           CH.sub.3 SCH.sub.2                                                                        COOCH.sub.2 CH(CH.sub.3)                                                      C.sub.2 H.sub.5                                   126    6-C.sub.2 H.sub.5 O                                                                    C.sub.2 H.sub.5                                                                           COOC(CH.sub.3)CH.sub.2                            127    6-C.sub.2 H.sub.5 O                                                                    C.sub.3 H.sub.7                                                                           COOC(CH.sub.3)CH.sub.2                            128    6-C.sub.2 H.sub.5 O                                                                    CH.sub.3 OCH.sub.2                                                                        COOC(CH.sub.3)CH.sub.2                            129    6-C.sub.2 H.sub.5 O                                                                    CH.sub.3 SCH.sub.2                                                                        COOC(CH.sub.3)CH.sub.2                            130    H (n = 0)                                                                              C.sub.2 H.sub.5                                                                           COOC.sub.2 H.sub.5                                131    H (n = 0)                                                                              C.sub.3 H.sub.7                                                                           COOC.sub.2 H.sub.5                                132    H (n = 0)                                                                              CH.sub.3 SCH.sub.2                                                                        COOC.sub.2 H.sub.5                                133    6-Cl     C.sub.2 H.sub.5                                                                           COOC.sub.2 H.sub.5                                134    6-F      C.sub.2 H.sub.5                                                                           COOC.sub.2 H.sub.5                                                                        Resin                                 135    6-F      CH.sub.3 SCH.sub.2                                                                        COOC.sub.2 H.sub.5                                136    6-CH.sub.3 O                                                                           C.sub.2 H.sub.5                                                                           COOC.sub.2 H.sub.5                                137    6-CH.sub.3 O                                                                           CH.sub.3 OCH.sub.2                                                                        COOC.sub.2 H.sub.5                                138    6-CH.sub.3 O                                                                           CH.sub.3 SCH.sub.2                                                                        COOC.sub.2 H.sub.5                                139    6-C.sub.2 H.sub.5 O                                                                    C.sub.2 H.sub.5                                                                           COOC.sub.2 H.sub.5                                140    6-C.sub.2 H.sub.5 O                                                                    CH.sub.3 SCH.sub.2                                                                        COOC.sub.2 H.sub.5                                140a   6-OH     CH.sub.3 SCH.sub.2                                                                        COOCH(CH.sub.3).sub.2                                                                     113                                   140b   6-OH     C.sub.2 H.sub.5                                                                           COOCH(CH.sub.3).sub.2                                                                     Resin                                 140c   6-Cl     CH.sub.3    COOCH.sub.2 CHCH.sub.2                                                                    144                                   140d   6-Cl     CH.sub.3    COOC(CH.sub.3)CH.sub.2                                                                    149                                   140e   6-Cl     C.sub.4 H.sub.9                                                                           COOC(CH.sub.3)CH.sub.2                                                                    132                                   140f   6-CH.sub.3 O                                                                           CH.sub.3 SCH.sub.2                                                                        COOCH(CH.sub.3)                                                                            60                                                               C.sub.2 H.sub.5                                   140g   6-CH.sub.3 O                                                                           CH.sub.3 SCH.sub.2                                                                        COOCH.sub.2 CH(CH.sub.3).sub.2                                                             89                                   140h   6-F      C.sub.2 H.sub.5                                                                           COOCH.sub.3 146                                   140i   6-F      C.sub.2 H.sub.5                                                                           COOC.sub.4 H.sub.9                                                                        103                                   140j   6-F      C.sub.2 H.sub.5                                                                           COOCH.sub.2 CH(CH.sub.3).sub.2                                                            Resin                                 140k   6-F      C.sub.2 H.sub.5                                                                           COOCH(CH.sub.3)                                                                            51                                                               C.sub.2 H.sub.5                                   140l   6-F      CH.sub.3 OCH.sub.2                                                                        COOCH(CH.sub.3).sub.2                                                                     143                                   ______________________________________                                    

Activity tests

Testing of preparations against HIV in cell culture

Description of the method:

medium: RMPI, pH 6.8

Complete medium additionally contains 20% fetal calf serum and 40 IU/mlrecombinant interleukin 2.

Cells

Lymphocytes, which have been isolated from fresh donor blood by means ofFicoll® gradient centrifugation, are cultured, for 36 hours at 37° C.and under 5% CO₂, in complete medium which additionally contains 2 g/mlphytohemagglutinin (Wellcome). After 10% DMSO has been added, the cellsare frozen at a cell density of 5×10⁶ and stored in liquid nitrogen. Forthe experiment, the cells are thawed, washed in the RPMI medium andcultured for 3 to 4 days in the complete medium.

Assay mixture

The test preparations were dissolved in DMSO at a concentration of 16.7mg/ml, and these solutions were diluted with complete medium to aconcentration of 1 mg/ml. 0.4 ml of medium was initially introduced into24-well multiwell plates. After 0.1 ml of the dissolved preparation hadbeen added to the upper row of the plate, a geometric dilution serieswas produced by transferring 0.1 ml on each occasion. Preparation-freecontrols contained 0.4 ml of complete medium containing 0.5% DMSO.

Lymphocyte cultures having a cell count of 5×10⁵ cells/ml were infectedby adding a 1/50 volume of the supernatant from HIV-infected lymphocytecultures. The titer of these culture supernatants was determined byend-point dilution to be 1-5×10⁶ infectious units/ml. After having beenincubated at 37° C. for 30 min, the infected lymphocytes werecentrifuged off and taken up once again in the same volume of medium.0.6 ml of this cell suspension was added to each of the wells in thetest plate. The assay mixtures were incubated at 37° C. for 3 days.

Evaluation

The infected cell cultures were examined under the microscope for thepresence of giant cells, which are indicative of active viralreplication in the culture. The lowest preparation concentration atwhich no giant cells occurred was determined and taken to be theinhibitory concentration against HIV. As a control, the supernatantsfrom the culture plates were assayed for the presence of HIV antigenusing an HIV antigen test in accordance with the manufacturer's(Organon) instructions.

Results

                  TABLE 4                                                         ______________________________________                                        Compound from  T-cell culture assay                                           Example No.    MIC EC.sub.50 (ng/ml)                                          ______________________________________                                         29            <8                                                              30            <40                                                             31            50                                                              34            <1                                                              35            <80                                                             38            <1                                                              39            8                                                               40            80                                                              42            <8                                                              43            <1                                                              44            <80                                                             52            <8                                                              54            40                                                              57            1                                                               58            10                                                              59            20                                                              60            40                                                              61            2                                                               62            80                                                              68            8                                                               78            <80                                                             84i           80                                                              84j           <80                                                             84l           80                                                              84o           80                                                              85            2                                                               86            1                                                               87            4                                                               88            <40                                                             90            <8                                                              91            2                                                               94            <8                                                              95            2                                                               96            80                                                              98            3                                                               99            <1                                                             100            4                                                              104            8                                                              108            <5                                                             110            4                                                              113            0.8                                                            114            1.6                                                            115            1.6                                                            124            <8                                                             134            8                                                              140a           40                                                             140b           <80                                                            140c           40                                                             140d           10                                                             140f           8                                                              140g           40                                                             140h           10                                                             140i           10                                                             140j           10                                                             140k           8                                                              140l           8                                                              ______________________________________                                    

Examination of the substances for their ability to inhibit HIV reversetranscriptase

The activity of the reverse transcriptase (RT) was determined using ascintillation proximity assay (SPA).

The reagent kit for the RT SPA was obtained from Amersham/Buchler(Braunschweig). The RT enzyme (derived from HIV and cloned in E. coli)was obtained from HT Biotechnology Ltd., Cambridge, UK.

Assay mixture

The test was carried out in accordance with the manufacturer's(Amersham) methods manual, with the following modifications:

Bovine serum albumin was added to the assay buffer to a finalconcentration of 0.5 mg/ml.

The test was carried out in Eppendorf tubes using an assay mixturevolume of 100 μl.

The manufacturer's RT concentrate (5000 U/ml) was diluted to an activityof 15 U per ml using 20 mM tris-HCl buffer, pH 7.2, 30% glycerol.

The assay mixtures were incubated for 60 min (37° C.).

After the reaction had been stopped and "developed" with the beadsuspension, 130 μl of assay mixture were transferred into 4.5 ml of 10mM tris-HCl buffer, pH 7.4, 0.15M NaCl and the tritium activity wasmeasured in a β-counter.

Testing the substances

In order to carry out a preliminary test of their inhibitory activity,the substances were dissolved in DMSO (stock solution, c=1 mg/ml) andtested when diluted 10⁻¹, 10⁻², 10⁻³ etc. in DMSO.

In order to determine IC₅₀ values, the stock solutions of inhibitor werefurther diluted in 50 mM tris-HCl buffer, pH 8, and tested at suitableconcentrations.

The concentration associated with 50% inhibition of the enzyme wasascertained from the plot of RT activity against log C_(inh).

The results of the investigation are shown in Table 5.

                  TABLE 5                                                         ______________________________________                                                      Reverse transcriptase                                           Compound from assay                                                           Example No.   IC.sub.50 (ng/ml)                                               ______________________________________                                         29           10-100                                                           34           10-100                                                           35           10                                                               38            5                                                               39           20                                                               40           10-100                                                           52           10-100                                                           57           10-100                                                           58           10-100                                                           59           18                                                               60           10                                                               61           10-100                                                           62           92                                                               68           16                                                               78           80                                                               84g          118                                                              84i          170                                                              84j          87                                                               84l          150                                                              85            8                                                               86           11                                                               87           27                                                               90            5                                                               91            4                                                               94           15                                                               96           16                                                               98           12                                                               99           11                                                              100           16                                                              104           35                                                              108            8                                                              110           10-100                                                          113            6                                                              114            7                                                              115           10                                                              125           15                                                              134            3                                                              140a          93                                                              140b          70                                                              140c          110                                                             140d          27                                                              140f          19                                                              140g          17                                                              140h           8                                                              140i          22                                                              140j          15                                                              140k          16                                                              140l          22                                                              ______________________________________                                    

What is claimed is:
 1. A compound of the formula I or Ia, ##STR8## or aphysiologically tolerated salt thereof, wherein, in formulae I and Ia:nis zero, one or two, R¹ is fluorine, chlorine, hydroxyl or C₁ -C₃-alkoxy, R² is C₁ -C₄ -alkyl which is unsubstituted or is substituted byhydroxyl, C₁ -C₄ -alkoxy or C₁ -C₄ -alkylthio, R³ is C₁ -C₆-alkyloxycarbonyl or C₂ -C₆ -alkenyloxycarbonyl, and X is oxygen, sulfuror selenium.
 2. A compound of the formula I or Ia as claimed in claim 1,wherein the substituents in the said formulae have the followingmeanings:n is zero or one, R¹ is fluorine, chlorine, hydroxyl or C₁ -C₃-alkoxy, R² is C₁ -C₄ -alkyl which is unsubstituted or is substituted byhydroxyl, C₁ -C₄ -alkoxy or C₁ -C₄ -alkylthio, R³ is C₁ -C₄-alkyloxycarbonyl or C₂ -C₄ -alkenyloxycarbonyl, and X is oxygen orsulfur.
 3. A compound of the formula I or Ia as claimed in claim 1,wherein the substituents in the said formulae have the followingmeanings:n is zero or one, R¹ is fluorine, chlorine, methoxy, ethoxy orpropoxy, R² is methylthiomethyl, ethyl or propyl, or C₁ -C₂ -alkyl whichis substituted by hydroxyl or C₁ -C₄ -alkoxy, R³ is C₁ -C₄-alkyloxycarbonyl or C₂ -C₄ -alkenyloxycarbonyl, and X is oxygen orsulfur.
 4. A compound of the formula I or Ia as claimed in claim 1,wherein the substituents in the said formulae have the followingmeanings:n is zero or one, R¹ is fluorine, chlorine, methoxy or ethoxy,R² is methylthiomethyl, ethyl or propyl, or C₁ -C₂ -alkyl which issubstituted by hydroxyl or C₁ -C₄ -alkoxy, R³ is C₁ -C₄-alkyloxycarbonyl or C₂ -C₄ -alkenyloxycarbonyl, and X is oxygen orsulfur.
 5. A process for preparing a compound of the formula I or Ia##STR9## wherein, in formulae I and Ia: n is zero, one or two,R¹ isfluorine, chlorine, hydroxyl or C₁ -C₃ -alkoxy, R² is C₁ -C₄ -alkylwhich is unsubstituted or substituted by hydroxyl, C₁ -C₄ -alkoxy or C₁-C₄ -alkylthio, R³ is C₁ -C₆ -alkyloxycarbonyl or C₂ -C₆-alkenyloxycarbonyl, and X is oxygen;which comprises the step ofreacting a compound of the formula II, ##STR10## defined as above, witha compound of the formula III,

    R.sup.3 --Z                                                (III)

wherein R³ is defined as above and Z is a leaving group.
 6. The processof claim 5, wherein Z is chlorine.
 7. The process of claim 5,additionally comprising the step of reacting a compound of the formula Ior Ia with a sulfurization reagent.
 8. A pharmaceutical composition forthe treatment of viral diseases which comprises an effective amount of acompound of the formula I or Ia as claimed in claim 1, or aphysiologically tolerated salt thereof together with a pharmaceuticallyacceptable carrier.
 9. A pharmaceutical composition which contains aneffective quantity of at least one compound of the formula I or Ia asclaimed in claim 1 or a physiologically tolerated salt thereof, togetherwith a pharmaceutically acceptable carrier.
 10. A method for thetreatment of human immunodeficiency disease which comprisesadministering to a host in need of such treatment a pharmaceuticalcomposition as claimed in claim
 9. 11. A method for the treatment ofhuman immunodeficiency disease which comprises administering to a hostin need of such treatment an effective amount of a compound as claimedin claim 1.